EP1689448B1 - Method for preparing dota-antibody conjugates - Google Patents
Method for preparing dota-antibody conjugates Download PDFInfo
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- EP1689448B1 EP1689448B1 EP04821464.7A EP04821464A EP1689448B1 EP 1689448 B1 EP1689448 B1 EP 1689448B1 EP 04821464 A EP04821464 A EP 04821464A EP 1689448 B1 EP1689448 B1 EP 1689448B1
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- Prior art keywords
- virus
- conjugate
- antibody
- disease
- dota
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
Definitions
- Metal ions such as radionuclides and transition metals, are useful for many diagnostic and therapeutic techniques.
- metal ions can be used as diagnostic or therapeutic agents, particularly with regard to radioimmunodetection, radioimmunotherapy, magnetic resonance imaging, photodynamic therapy or other similar modalities.
- these techniques require specific targeting of the metal ion to a selected tissue.
- Targeting molecules such as antibodies or binding molecules
- targetable molecules such as haptenic peptides
- Antibody-chelator conjugates or peptide-chelator conjugates are useful because the chelator moiety of these conjugates can bind metal ions to form a metal chelate.
- Antibody-chelator conjugates can be used to directly target the metal chelate to a targeted tissue.
- peptide-chelator conjugates are typically used in combination with a bi-specific binding molecule.
- the peptide-chelator conjugates may include a hapten that is recognized by a bi-specific binding molecule that also recognizes the targeted tissue.
- the bi-specific binding molecule can be used to localize the peptide-chelator conjugate ( i . e ., the targetable molecule) to the targeted tissue.
- DOTA-peptide conjugates rely on formation of stable amide bonds between the DOTA molecule and one or more ⁇ -amino groups on a lysine residue of the peptide.
- the previously described methods of forming DOTA-peptide conjugates may also result in the formation of unstable DOTA-ester bonds with the peptide, ( e.g ., at the hydroxyl group of a serine, threonine, or tyrosine), because DOTA-peptide synthesis reactions are typically performed at a high pH (> 8.0), any unstable ester bonds would be expected to be readily hydrolyzed.
- DOTA-peptide synthesis reactions typically result in a low substitution ratio of DOTA per peptide.
- a synthesis reaction using a molar ratio of DOTA to peptide of ⁇ 100:1 typically results in a substitution ratio of less than four (4) DOTA molecules per peptide in the synthesized conjugate.
- a substitution ratio of less than four (4) DOTA molecules per peptide in the synthesized conjugate.
- a method of preparing a conjugate that includes reacting DOTA and an antibody to form the conjugate, and subsequently reacting the conjugate with a quenching agent.
- the conjugate is formed by an amino acyl reaction.
- the chelating agent is activated by reacting the chelating agent with an acylating reagent before, simultaneously, or after reacting the chelating agent and the protein to form the conjugate.
- the chelating agent is reacted with an acylating reagent before reacting the chelating agent and the protein.
- the activated chelating agent may include an acyl azide, an acyl cyanide, an acyl halide, an activated acyl ester, an enol ester, an isoxazolium agent, an isothiocyanate, an N-acyl imidazote, an N-acyl pyrazole, an N-acyl triazole, a carbodiimide, a mixed carbonic anhydride, a mixed carboxylic anhydride, a mixed phosphonic anhydride, a mixed phosphonic anhydride, or a mixture of the aforementioned compounds.
- the quenching agent is hydroxylamine or salt thereof (e.g ., hydroxylamine hydrochloride or another hydroxylamine-acid salt), or mixtures of these compounds.
- the chelating agent may be used to chelate any useful metal species.
- the chelating agent may be used to chelate a radionuclide, and as such, the chelating agent may be radiolabeled.
- Useful radionuclides may include 47 Sc, 51 Mn, 52 Mn, 52 Fe, 59 Fe, 55 Co, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 72 As, 77 As, 83 Sr, 89 Sr, 86 Y, 89 Zr, 90 Y, 94 Tc, 94m Tc, 99 Mo, 99m Tc, 105 Pd, 105 Rh, 111 Ag, 110 In, 111 In, 123 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir
- the antibody may be monoclonal or polyclonal. It may be desirable to select a murine, chimeric, primatized, humanized, or human antibody to prepare the conjugate. Multispecific antibodies (e.g ., bi-specific antibodies) or multivalent antibodies may be particular desirable for preparing the conjugates. Trivalent or tetravalent binding molecules may be used.
- the antibody or antibody fragment includes at least one arm that specifically binds a targeted tissue, for example targeted tissues that include an antigen associated with a malignant disease, a cardiovascular disease, an infectious disease, an inflammatory, disease, an autoimmune disease, or a neurological disease.
- Specific antigens may include colon-specific antigen-p (CSAp), carcinoembryonic antigen (CEA), CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD80, HLA-DR, la, li, MUC 1, MUC 2, MUC 3, MUC 4, NCA, EGFR, HER 2/neu, PAM-4, TAG-72, EGP-1, EGP-2, A3, KS-1, Le(y), S100, PSMA, PSA, tenascin, folate receptor, VEGF, PIGF, ILGF-1, necrosis antigens, IL-2, IL-6, T101, MAGE, or a combination of these antiges.
- CSAp colon-specific antigen-p
- CEA carcinoembryonic antigen
- CD4 CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD
- antigens may include carcinoembryonic antigen, tenascin, epidermal growth factor receptor, platelet derived growth factor receptor, fibroblast growth factor receptors, vascular endothelial growth factor receptors, gangliosides, HER/2neu receptors and combinations of these antigens.
- the antibody may recognize particular antigens associated with an infectious disease such as a bacterial disease, fungal disease, parasitic disease, viral disease, or combinations of these diseases.
- infectious diseases may include those caused by a pathogen selected from Microsporum, Trichophyton, Epidermophyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Candida albicans, human immunodeficiency virus (HIV), herpes virus, cytomegalovirus, rabies virus, influenza virus, hepatitis B virus, Sendai virus, feline leukemia virus, Reo virus, polio virus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein
- the antibody used to form the conjugate may also recognize antigens associated with an autoimmune disease, such as idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcalnephritis, erythema nodosurn, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spond
- the antibody selected to prepare the conjugate may also recognize an antigen associate with a cardiovascular disease.
- the antibody may also be selected to recognize antigens associated with myocardial infarction, ischemic heart disease, atheroschlerotic plaques, fibrin clots, emboli, or a combination of these cardiovascular diseases.
- the antibody may also recognize an antigen specific for granulocytes, lymphocytes, monocytes, or a mixture of these cell types, where the presence of these cell types is indicative of cardiovascular disease.
- the antibody or antibody fragment selected for preparing the conjugate may also specifically bind an antigen associated with a neurological disease, (e.g., the antibody or fragment may specifically bind antigens associated with an amyloid deposit).
- the selected antibody or fragment used to prepare the conjugate may recognize an antigen associated with a multiple myeloma, a B-cell malignancy, a T-cell malignancy, or combinations of these diseases.
- Particular B-cell malignancies may include forms of B-cell lymphomas, aggressive forms of B-cell lymphomas, chronic leukemias, and acute lymphatic leukemias.
- Other malignancies may include non-Hodgkin's lymphoma or Hodgkin's lymphoma.
- the antibody or fragment may also recognize an antigen associated with a solid tumor, including a melanoma, a carcinoma, a sarcoma, a glioma, or combinations of these solid tumors.
- a solid tumor including a melanoma, a carcinoma, a sarcoma, a glioma, or combinations of these solid tumors.
- carcinomas include renal carcinomas lung carcinomas, intestinal carcinomas, stomach carcinomas, breast carcinomas, prostrate cancers, and ovarian carcinomas.
- Cytokines or immunomodulators may also be selected to prepare the conjugate. Suitable cytokines or immunomodulators include IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, IL-21, interferon- ⁇ , interferon- ⁇ , interferon- ⁇ , G-CSF, and GM-CSF, or mixtures of these molecules.
- the method includes reacting DOTA and an antibody to form the conjugate, and subsequently hydrolyzing any non-stable bonds formed between the chelating agent and the protein.
- Suitable methods for hydrolyzing the non-stable bonds may include chemical methods by treating the sample with hydroxylamine or a salt thereof.
- the method includes reacting a chelating agent and an acylating agent to form an activated chelating agent; reacting the activated chelating agent and a protein to form the conjugate; and reacting the conjugate and a quenching agent to hydrolyze any non-stable bonds.
- a conjugate prepared by the aforementioned methods where the conjugate is substantially free of non-stable bonds between the chelating agent and the protein.
- a conjugate prepared by the aforementioned method may be substantially free of non-amide bonds or ester bonds between the chelating agent and the protein.
- the conjugate may incorporate a label (e.g ., a radiolabel) very efficiently after the conjugate has been stored in solution for an extended period of time.
- a label will be incorporated with an incorporation yield of no less than about 97% when the label is reacted with a conjugate synthesized by the aforementioned methods, even after the conjugate is stored for no less than six months at about 4°C.
- conjugates synthesized by the aforementioned methods are substantially free of non-stable bonds or ester bonds, typically no more than about 3% of the chelating agent is hydrolyzed from the conjugate, even after the conjugate is stored for no less than six months at about 4°C.
- the therm 'protein' is understood to refer to antibodies.
- the proteins useful in the following processes are antibodies (monoclonal or polyclonal), that contains sufficient amine residues that can be acylated, in order to form a chelator-protein conjugate.
- the amine residues can be those naturally present in a protein chain (e.g ., lysine or ornithine), or they can be amino groups placed within a protein chain artificially, ( e.g ., co-polymers such as KEPY).
- the described methods may be used for any synthesis method that includes conjugating a chelating agent (i .e., chelator) to an amino containing polymeric material using an acylation reaction on a free amino group.
- Proteins often contain groups other than amino groups that can be acylated during the amino acylation reaction. Such groups are most often hydroxyl- or thio- (mercapto) groups, but can be any functional group that can mimic the nucleophilic nature of the amino group.
- the inventors have found that attempts to attach chelating agents to proteins at amino groups (e.g ., the ⁇ -amino group of a lysine residue), may result in the production of amorphous products, wherein the chelating agents are also attached at other functional groups, (e.g ., hydroxyl groups on residues such as tyrosine, threonine or serine; thiol groups of cysteine; and imidazoyl groups of histidine).
- amino groups e.g ., the ⁇ -amino group of a lysine residue
- the chelating agents are also attached at other functional groups, (e.g ., hydroxyl groups on residues such as tyrosine,
- the inventors encountered the following problem in synthesizing a DOTA-MAb conjugate. See Figure 3 , Scheme 1.
- the chelating agent may be activated in situ and then used for protein coupling, but reaction schemes wherein the chelating agent intermediate is first separated and/or purified are also contemplated as within the scope of the present methods.
- the activated chelating agent in this case DOTA
- the multifunctional protein in this case an antibody
- radiolabeled DOTA-MAb conjugate must be purified prior to administration, to separate the desired conjugate product from low molecular weight products (e.g ., In-111/Y-90 chelated to a hydrolyzed DOTA molecule).
- the purification step requires additional handling of radioactive materials and results in additional cost, and further, may result in the introduction of contaminants or may render the product commercially unviable.
- the presence of a small amount of DOTA linked to the antibody by a non-amide bond may lead, over time, in the aqueous environment in which the DOTA-MAb was stored, to a dissociation of that unstably bound DOTA.
- that fraction of the DOTA that was conjugated to MAb on tyrosine, threonine, serine, or histidine residues by an ester or imidazoyl bond may hydrolyze over time and release free DOTA into the DOTA-MAb solution.
- the slow accumulation of free DOTA in the DOTA-MAb solution may have lead to a competition of the free DOTA against the DOTA-MAb when the In-111 or Y-90 was admixed in the radiolabeling reaction.
- the free DOTA may out-compete the DOTA-MAb for binding to radioactive label (i.e ., In-111 and Y-90), and a mixture of In-111- or Y-90-DOTA and in-111-DOTA-MAb or Y-90-DOTA-MAb, respectively, may have resulted.
- the repurified fraction incorporated radiolabel with a yield of > 90%, whereas the non-repurified fraction incorporated radiolabel with a yield of ⁇ 80%.
- the size-exclusion repurification step removes any free DOTA that forms over the storage period, and allows a near-full incorporation of radiometal into the DOTA-MAb, as when the DOTA-MAb conjugate was first synthesized.
- any DOTA that is bound by unstable bonds can be removed prior to storage.
- the conjugate is subjected to a short reaction with hydroxylamine to cleave or hydrolyze unstable bonds. This reaction ensures that any unstably bound DOTA (e.g ., hydroxyl-linked DOTA) is cleaved from the DOTA-MAb conjugate, and only stably bound DOTA ( e.g ., amide-linked DOTA-MAb) remains bound to the conjugate in preparation for storage.
- the described method may be useful for a variety of chelating agents and related peptide conjugates.
- Therapeutic and diagnostic chelating agents, peptides, chelator- (and/or chelate-) peptide conjugates, and methods for synthesizing such conjugates have been described. See U.S. 4,472,509 ; U.S. 4,678,667 ; U.S. 4,824,986 ; U.S. 4,831,175 ; U.S. 4,861,869 ; U.S. 5,057,302 ; U.S. 5,082,928 ; U.S. 5,082,930 ; U.S. 5,087,696 ; U.S. 5,099,069 ; U.S.
- the MAb used to form the DOTA-MAb conjugate was a complementarity-determining region-grafted [humanized] LL2 (hLL2; anti-CD22).
- LL2 antibodies are described in U.S. 5,789,544 ; U.S. 6,187,287 ; U.S. 2002-0102254 , and U.S. application serial no. 10/446,689 , all of which are incorporated by reference in their entireties.
- the antibody used to form the DOTA-MAb conjugate was hPAM4, which is an anti-MUC-1 antibody. See U.S. applications 10/461,885 filed June 16, 2003 and 60/388,314 filed June 14, 2002 , both of which are incorporated by reference in their entireties.
- this low molecular weight material in the vial lot of hLL2-DOTA increased during storage.
- This low molecular weight material was able to bind to Y-90 added during radiolabeling, and inhibit full binding of added Y-90 to the DOTA-hLL2 conjugate.
- a certain percentage of the DOTA may be dissociated or detached or from the antibody during the storage period, which is consistent with a small percentage of the attached chelating agent originally being bound by unstable bonds (e.g., esters of hydroxyl groups), rather than by stable bonds (e.g. , amides of amine groups).
- HPLC Y-90-DOTA-hLL2 (%)
- HPLC Free Y-90 (%)
- ITLC Free Y-90 (%) 0 99.5-99.5 0.5-0.5 1.1-1.2 1 98.3-98.4 1.6-1.7 2.3-2.4 2 98.6-99.0 1.0-1.4 1.7-1.8 3 97.2-97.4 2.6-2.8 1.2-1.8 6 99.0-100 0.0-1.0 1.0-1.0 12 97.8-99.0 1.0-2.2 1.4-2.4
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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EP15002212.7A EP2962699A3 (en) | 2003-12-01 | 2004-12-01 | Improved method for preparing conjugates of proteins and chelating agents |
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US52604403P | 2003-12-01 | 2003-12-01 | |
PCT/US2004/040046 WO2005084179A2 (en) | 2003-12-01 | 2004-12-01 | Improved method for preparing conjugates of proteins and chelating agents |
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EP15002212.7A Division EP2962699A3 (en) | 2003-12-01 | 2004-12-01 | Improved method for preparing conjugates of proteins and chelating agents |
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EP1689448A2 EP1689448A2 (en) | 2006-08-16 |
EP1689448A4 EP1689448A4 (en) | 2010-10-13 |
EP1689448B1 true EP1689448B1 (en) | 2015-07-29 |
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EP04821464.7A Expired - Fee Related EP1689448B1 (en) | 2003-12-01 | 2004-12-01 | Method for preparing dota-antibody conjugates |
EP15002212.7A Withdrawn EP2962699A3 (en) | 2003-12-01 | 2004-12-01 | Improved method for preparing conjugates of proteins and chelating agents |
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EP15002212.7A Withdrawn EP2962699A3 (en) | 2003-12-01 | 2004-12-01 | Improved method for preparing conjugates of proteins and chelating agents |
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US (1) | US7259249B2 (ja) |
EP (2) | EP1689448B1 (ja) |
JP (1) | JP4912153B2 (ja) |
WO (1) | WO2005084179A2 (ja) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8877901B2 (en) | 2002-12-13 | 2014-11-04 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US7591994B2 (en) | 2002-12-13 | 2009-09-22 | Immunomedics, Inc. | Camptothecin-binding moiety conjugates |
US7524570B2 (en) * | 2005-10-13 | 2009-04-28 | Hitachi Global Storage Technologies Netherlands B.V. | Perpendicular magnetic recording system and medium with high-moment corrosion-resistant “soft” underlayer (SUL) |
CA2711426C (en) | 2008-01-08 | 2018-05-22 | Lantheus Medical Imaging, Inc. | N-alkoxyamide conjugates as imaging agents |
US20100247484A1 (en) * | 2009-03-31 | 2010-09-30 | Heinrich Barchet | Combination therapy of an afucosylated antibody and one or more of the cytokines gm csf, m csf and/or il3 |
US8877157B2 (en) * | 2009-07-08 | 2014-11-04 | Lantheus Medical Imaging, Inc. | N-alkoxyamide conjugates as imaging agents |
IN2012DN03354A (ja) | 2009-12-02 | 2015-10-23 | Immunomedics Inc | |
NO331080B1 (no) * | 2010-01-29 | 2011-09-26 | Nordic Nanovector As | Radioimmunkonjugater, farmasøytiske sammensetninger og kit omfattende det samme og anvendelse derav |
RU2577125C2 (ru) * | 2010-02-10 | 2016-03-10 | Фуджифилм Ри Фарма Ко., Лтд. | Меченное радиоактивным металлом антитело против кадгерина |
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US20160130328A1 (en) * | 2013-06-17 | 2016-05-12 | Emory University | Pathogen Binding Agents Conjugated to Radioisotopes and Uses in Imaging and Therapeutic Applications |
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EP3286224A4 (en) | 2015-04-22 | 2018-11-14 | Immunomedics, Inc. | Isolation, detection, diagnosis and/or characterization of circulating trop-2-positive cancer cells |
WO2017161356A1 (en) * | 2016-03-18 | 2017-09-21 | Wake Forest University | Compounds, compositions and associated methods using zirconium-89 in immuno-positron emission tomography |
CA3063983A1 (en) | 2017-05-24 | 2018-11-29 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use in the treatment of cancer |
JPWO2021033530A1 (ja) * | 2019-08-21 | 2021-02-25 | ||
WO2023190402A1 (ja) * | 2022-03-30 | 2023-10-05 | 日本メジフィジックス株式会社 | 複合体の製造方法 |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4472509A (en) | 1982-06-07 | 1984-09-18 | Gansow Otto A | Metal chelate conjugated monoclonal antibodies |
US5556982A (en) | 1985-01-14 | 1996-09-17 | Neorx Corporation | Metal radionuclide labeled proteins for diagnosis and therapy |
US4824986A (en) | 1985-04-26 | 1989-04-25 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Metal chelate protein conjugate |
NZ212437A (en) | 1985-06-17 | 1992-06-25 | Mark Philip Best | Site-directed antibody conjugates, and their preparation |
US4678667A (en) | 1985-07-02 | 1987-07-07 | 501 Regents of the University of California | Macrocyclic bifunctional chelating agents |
GB8603537D0 (en) | 1986-02-13 | 1986-03-19 | Parker D | Conjugate compound |
US5271927A (en) | 1986-02-13 | 1993-12-21 | Celltech Limited | Antibody conjugates with macrocyclic ligands |
US5082930A (en) | 1986-05-29 | 1992-01-21 | Mallinckrodt Medical, Inc. | Coupling agents for joining radionuclide metal ions with biologically useful proteins |
US4861869A (en) | 1986-05-29 | 1989-08-29 | Mallinckrodt, Inc. | Coupling agents for joining radionuclide metal ions with biologically useful proteins |
US5099069A (en) | 1986-09-05 | 1992-03-24 | Gansow Otto A | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
US4831175A (en) | 1986-09-05 | 1989-05-16 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
US5246692A (en) | 1986-09-05 | 1993-09-21 | The United States Of America As Represented By The Secretary Of Health And Human Services | Backbone polysubstituted chelates for forming a metal chelate-protein conjugate |
US5057302A (en) | 1987-02-13 | 1991-10-15 | Abbott Laboratories | Bifunctional chelating agents |
WO1988007553A1 (en) * | 1987-03-26 | 1988-10-06 | Teijin Limited | Process for preparing antibody complex |
US5217704A (en) | 1987-11-06 | 1993-06-08 | Abbott Laboratories | Methods and materials for the preparation of metal labelled antibody solutions |
US5130118A (en) | 1987-11-06 | 1992-07-14 | Abbott Laboratories | Methods and materials for the preparation of metal labelled antibody solutions |
US5612016A (en) | 1988-04-01 | 1997-03-18 | Immunomedics, Inc. | Conjugates of antibodies and bifunctional ligands |
US5075099A (en) | 1988-05-31 | 1991-12-24 | Neorx Corporation | Metal radionuclide chelating compounds for improved chelation kinetics |
DE353450T1 (de) | 1988-06-24 | 1990-09-06 | The Dow Chemical Co., Midland, Mich. | Macrocyclische bifunktionelle chelatbildner, komplexe davon und ihre konjugierten antikoerper. |
US5756065A (en) | 1988-06-24 | 1998-05-26 | The Dow Chemical Company | Macrocyclic tetraazacyclododecane conjugates and their use as diagnostic and therapeutic agents |
US5808003A (en) | 1989-05-26 | 1998-09-15 | Perimmune Holdings, Inc. | Polyaminocarboxylate chelators |
US5112953A (en) | 1989-12-29 | 1992-05-12 | Neorx Corporation | Radiolabeled proteins for diagnostic or therapeutic use |
US5124471A (en) | 1990-03-26 | 1992-06-23 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Bifunctional dtpa-type ligand |
US5367080A (en) | 1990-11-08 | 1994-11-22 | Sterling Winthrop Inc. | Complexing agents and targeting radioactive immunoreagents useful in therapeutic and diagnostic imaging compositions and methods |
US5310535A (en) | 1992-04-24 | 1994-05-10 | The Dow Chemical Company | Carboxamide modified polyamine chelators and radioactive complexes thereof for conjugation to antibodies |
JPH05344899A (ja) | 1992-06-11 | 1993-12-27 | Kokuritsu Yobou Eisei Kenkyusho | C型肝炎ウイルス外被タンパク質の産生法 |
US5760191A (en) | 1993-02-05 | 1998-06-02 | Nycomed Imaging As | Macrocyclic complexing agents and targeting immunoreagents useful in therapeutic and diagnostic compositions and methods |
CA2195557C (en) | 1994-08-12 | 2006-10-17 | Shui-On Leung | Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells |
WO2003048207A2 (en) * | 2001-11-28 | 2003-06-12 | Immunomedics, Inc. | Anti-dota antibody |
-
2004
- 2004-12-01 EP EP04821464.7A patent/EP1689448B1/en not_active Expired - Fee Related
- 2004-12-01 JP JP2006542675A patent/JP4912153B2/ja not_active Expired - Fee Related
- 2004-12-01 EP EP15002212.7A patent/EP2962699A3/en not_active Withdrawn
- 2004-12-01 WO PCT/US2004/040046 patent/WO2005084179A2/en not_active Application Discontinuation
- 2004-12-01 US US11/000,500 patent/US7259249B2/en not_active Expired - Fee Related
Non-Patent Citations (4)
Title |
---|
KUKIS ET AL: "Optimized conditions for chelation of yttrium-90-DOTA immunoconjugates.", THE JOURNAL OF NUCLEAR MEDICINE, vol. 39, no. 12, 1 December 1998 (1998-12-01), pages 2105 - 2110, XP055039607, ISSN: 0161-5505 * |
MICHAEL R. LEWIS ET AL: "An Improved Method for Conjugating Monoclonal Antibodies with N -Hydroxysulfosuccinimidyl DOTA", BIOCONJUGATE CHEMISTRY, vol. 12, no. 2, 1 March 2001 (2001-03-01), pages 320 - 324, XP055039606, ISSN: 1043-1802, DOI: 10.1021/bc0000886 * |
MIN LI ET AL: "SYNTHESIS, METAL CHELATE STABILITY STUDIES, AND ENZYME DIGESTION OF A PEPTIDE-LINKED DOTA DERIVATIVE AND ITS CORRESPONDING RADIOLABELED IMMUNOCONJUGATES", BIOCONJUGATE CHEMISTRY, ACS, WASHINGTON, DC, US, vol. 4, no. 4, 1 July 1993 (1993-07-01), pages 275 - 283, XP000382741, ISSN: 1043-1802, DOI: 10.1021/BC00022A005 * |
SALAKO ET AL: "Effects of radiolysis on yttrium-90-labeled Lym-1 antibody preparations.", THE JOURNAL OF NUCLEAR MEDICINE, vol. 39, no. 4, 1 April 1998 (1998-04-01), pages 667 - 670, XP055039610, ISSN: 0161-5505 * |
Also Published As
Publication number | Publication date |
---|---|
WO2005084179A3 (en) | 2006-03-16 |
JP2007535492A (ja) | 2007-12-06 |
US7259249B2 (en) | 2007-08-21 |
EP1689448A2 (en) | 2006-08-16 |
EP2962699A2 (en) | 2016-01-06 |
EP2962699A3 (en) | 2016-04-06 |
WO2005084179A2 (en) | 2005-09-15 |
US20050191239A1 (en) | 2005-09-01 |
JP4912153B2 (ja) | 2012-04-11 |
EP1689448A4 (en) | 2010-10-13 |
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